Rapid Onset of Action Seen for Experimental Antidepressants

Action Points

Explain to patients who ask that the drugs described here have only been tested in animal models of depression and have not yet been tested in clinical trials in humans.

MONTREAL, Sept. 5 -- Antidepressants that directly enhance serotonin signaling appear to have a much faster onset of action in animal models of depression than selective serotonin reuptake inhibitors (SSRIs), said investigators here.

Rats given one of two serotonin-(HT4) agonists -- a new class of drug -- showed behaviors and brain changes within three days that were suggestive of antidepressant effects that would take two to three weeks to achieve with an SSRI, reported Guillaume Lucas, Ph.D., of McGill University, and colleagues in the Sept 6 issue of Neuron.

The authors provide "an extensive and convincing data set" suggesting that this new class of molecules is fasting-acting and potentially efficacious, but whether they will see the light of day as therapies for human depression is still unknown, cautioned Ronald S. Duman, Ph.D., of Yale, in an accompanying editorial.

"These agents will require extensive testing in clinical trials for confirmation, because of limitations inherent in rodent models of depression and antidepressant response and because of potential side effects," Dr. Duman wrote.

"It seems likely," he continued "that these new results presented in this report will stimulate efforts to develop safe 5-HT4 agonists that enter the brain and that can be used to further test this hypothesis in preclinical and ultimately clinical trials that could lead to a much needed novel, rapid, and improved class of antidepressants."

Unlike SSRIs, which interfere with the reuptake, or recycling of serotonin, 5-HT4 agonists increase the firing of serotonergic neurons, achieving their maximal effect within about three days.

In contrast, SSRIs "increase synaptic levels of 5-HT relatively quickly (hours or days), but there is a delay in therapeutic response (weeks or months) due to the likely requirement for adaptations at both pre- and postsynaptic sites," Dr. Duman wrote.

Dr. Lucas and colleagues first compared the effects of two 5-HT4 agonists, RS 67333 and prucalopride, with the SSRI citalopram (Celexa) in rats subjected to the forced swim test. The test measures the duration of immobility of the subjects as a surrogate for depression.

They found that both 5-HT4 agonists significantly reduced the time of immobility by about 50% compared with controls, whereas citalopram reduced immobility time by about 23% (P<0.05 for both 5-HT4 agonists vs. citalopram).

The investigators then evaluated the effects of three days of treatment with the experimental agents to see whether they could elicit the same functional, morphological, and molecular changes in the brain as seen with other antidepressants.

They found that the action of the drugs on the 5-HT4 receptor "deeply modified" serotonin transmission by enhancing firing of dorsal raphe neurons in the hippocampus. In addition, three days of treatment also significantly promoted neurogenesis in the subgranular zone of the dentate gyrus of the hippocampus, an effect normally seen after a minimum of two weeks of treatment with classical antidepressants or SSRIs.

In behavioral experiments, RS 67333 was significantly more effective than citalopram at suppressing activity in a rat model of hyperlocomotion, and the 5-HT4 agonist had an effect similar to that of citalopram at reducing sucrose intake of rats subjected to stress. (Rats under stress typically consume significantly more sucrose than in normal conditions).

However, when the authors compared RS 67333 with fluoxetine (Prozac) in rat models of anxiety, they found that neither agent had a significant effect.

"Overall, the results presented here show a clear potential for 5-HT4 agonists as putative antidepressants with a rapid onset of action," the authors wrote. "According to the different experimental models studied, they may act four to seven times more rapidly than classical antidepressants and possibly with greater efficacy."

They noted that RS 67333 and prucalopride are both capable of crossing the blood-brain barrier, raising the prospect of further animal and human studies.

"Although much work remains to be done, the side effects of 5-HT4 receptor agonists could be fewer or different relative to SSRIs, which would influence the quality of life and treatment compliance of patients taking antidepressant drugs," Dr. Duman wrote in his editorial.

"Most notably, libido is decreased in many SSRI-treated patients, and it is possible that 5-HT4 agonists may not cause similar effects, although this will require further testing," he continued. "Expression of 5-HT4 receptors in the prefrontal cortex and hippocampus is associated with increased learning, memory, and cognition, another potential beneficial effect of 5-HT4 agonists."

Dr. Duman also noted, however, that because 5-HT4 receptors are also expressed in the gastrointestinal system and the heart, 5-HT4 agonists could have unforeseen adverse effects.

The study by Dr. Lucas and colleagues was supported by the Canadian Institutes of Health Research. Dr. Lucas received a fellowship from Wyeth Ayerst Canada. No other author conflicts of interest were listed.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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